Posted
by
Soulskill
on Wednesday March 17, 2010 @10:02AM
from the wolverine-explained dept.

telomerewhythere writes "A quest that began over a decade ago with a chance observation has reached a milestone: the identification of a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice long thought to have been lost through evolution and reserved for creatures like flatworms, sponges, and some species of salamander. 'Unlike typical mammals, which heal wounds by forming a scar, these mice begin by forming a blastema, a structure associated with rapid cell growth and de-differentiation as seen in amphibians. According to the Wistar researchers, the loss of p21 causes the cells of these mice to behave more like embryonic stem cells than adult mammalian cells, and their findings provide solid evidence to link tissue regeneration to the control of cell division. "Much like a newt that has lost a limb, these mice will replace missing or damaged tissue with healthy tissue that lacks any sign of scarring," said the project's lead scientist.' Here is the academic paper for those with PNAS access."

However, his healing factor results in massive scar tissue causing his appearance to be severely disfigured. An unanticipated side effect of the therapy was a rapid acceleration of cancerous tumors as well, causing them to quickly spread across his entire body as soon as his powers fully activated.

Except without the funny one liners, awesome assasin skills, teleporter, or probably the rivalry with wolverine. I suppose you could wear the costume though and get in a fight with a real wolverine.

You are correct. In point of fact, around 90% of the time when you hear that "X gives you cancer" what you should instead read it as is "X causes cancer to happen sooner". Usually this means that exposure to risk factor X reduces your ability to fight off cancer. You've probably got a few carcinogenic cells in you right now that are going to be killed off before they do you any harm. Obviously this doesn't apply in every single case - ionizing radiation falls into that other 10% that really does cause cancer directly - but when you see cancer linked to, say, stress, that falls under the other 90%.

I don't think that tissue regeneration will cause cancer to happen more frequently, for two reasons. The first is that the healing process in humans already accelerates cancer. As do certain immune responses. Essentially, every bit of damage you pick up over your lifetime accelerates the inevitable rise of carcinogenesis by some tiny amount. Regeneration, done correctly, probably won't worsen this.

The second reason is that the reason mammals don't regenerate naturally has to do with speed, not safety. The healing process in mammals essentially slaps a quick patch over the damage in order to get you healthy sooner; we call this patch a scar. Regenerating vertebrates (amphibians, some reptiles) take longer to heal, but heal more completely, which is substantially more viable when you're cold blooded and can go a few days without more food. At some point in our distant evolutionary past, scarring became a more viable approach to damage, as it fixed us up sooner, so selection pressure favored the scarring over the regenerating. Lack of regeneration in humans is a matter of what worked in the wild for our ancestors, not what works today, where the injured have plenty of time to recuperate, and don't run the risk of starvation or predation.

As you demonstrate you already know, cancer prevention is partly about restricting the uncontrolled growth of cells; a tumor is cells growing without controls, so many natural defenses against cancer place controls on cell growth, sometimes by inhibiting healthy cell growth as well.

Turning off a gene like p21 is probably going to impact your body's ability to control and respond to cancer:

It's interesting, because p53 is a major regulator of p21 expression, and p21 itself is a major player in regulating cell cycle progression into S-phase, thus controlling cell replication. p53 knockouts, on the other hand, are extremely prone to cancer, as p53 is one of the most important tumor-suppressor genes.

The paper is interesting because the authors demonstrate that two separate strains of mice that contain a p21 deficiency can both regenerate differentiated tissue (measured by looking at ear-hole closure), supporting the link between p21/cell cycle progression and tissue regeneration. Whether this is of consequence therapeutically is a different story, but I'd be very interested to see the same study repeated in wild-type mice being fed or injected a small molecule p21 inhibitor.

Of course the caveat to using mice to judge how a gene affects long-term development of cancer is that there really is no "long-term" on a human scale in mouse studies, since they only live about 3 years at most.

I'm also not entirely familiar with the effect of p21-deficiency in cases where major tumor suppressors are deregulated or otherwise deficient. It is feasible that in the absence of further regulation, the absence of a major cell cycle checkpoint will lead to a more severe phenotype, whether in terms of being more tumor prone, or development of more aggressive tumors.

Primarily because they are cheap to breed and raise, take up very little space, reach maturity quickly, and people usually don't freak out about experiments on mice the same way they would on (say) primates.

They are also an acceptable human analogue in that they generally respond to medication and treatments similarly to how a human would; there are certainly other animals which are better models, but there are logistical, economic and public relations issues with trying to keep hundreds of chimpanzees in order to punch holes in their ears.

You could probably keep 10+ mice, quite comfortably, in the volume of space an adult pig takes up. I could probably keep 100 caged mice in my office, with ample room for them to run around and live relatively normal mouse-lives; whereas a single pig would probably be tearing this place up and demanding half* its body weight in food everyday. It would be ridiculous.

No, the logical solution here is to find out which gene we need to turn off to make mice taste like pork and just go from there.

In fact, the researchers saw an increase in apoptosis in MRL mice -- also known as programmed cell death -- the cell's self-destruct mechanism that is often switched on when DNA has been damaged. According to Heber-Katz, this is exactly the sort of behavior seen in naturally regenerative creatures.

Does that mean shorter lifespan for the lifeform overall, or does it simply mean that individual cells will die regularly and then quickly be regenerated?

As long as p53 remains correctly active and functional, p21 inhibition has a potential to become a major cure treatment for a variety of ailments, from third degree burns to diabetes... up to any number of currently untreatable problems. Such a promising cure could possibly be upgraded, research pending, to a magic bullet vaccine status.

While in general I agree with your statement about not wading into something I don't know about, I'm going to do it anyway:P

p21 was evolved out of mammals, if it's got this wondrous healing ability attached to it, it makes very little sense for it to have not had a *major* impact on the fitness of creatures without it unless it also gives some major benefit by having it present. I'm not going to claim it protects against cancer, instead merely make a vague statement along the lines of "we'd better watch o

The cancer concern is a legitimate one. These p21 knockouts are lab mice kept in clean conditions. They may not develop cancers in a three year span, but that demonstrates little about the oncogenic potential in humans.

I'm assuming there is some evolutionary reason for curtailing a vigorous healing response. It maybe to reduce the cancer rate, but it could just as simply be something else very important - regulation of immune response for example.

Presumably in the past there must have been some evolutionary advantage to developing scars rather than regrowing a new limb.

Speed is one possible reason. Another may be that a lot of scars are caused by things that persist (e.g. splinters, fibers, parasites), and it is potentially useful to encapsulate them in fibrous tissue, rather than regenerating normal tissue.

Of course PETA believes any sort of servitude by animals is the same as slavery. They'll never be happy. After all, if they ever got everything they wanted they'd have to find something useful to do with their lives.

The worst part of it is, science believes that cats 'self domesticated' [wikipedia.org]. If anything, denying humans the right to keep cats as pets is animal abuse, since it is denying them an adaptation they developed themselves.

if it did thought, would you. I mean if you could grow any penis size you wanted but you had to cut your original one off to get it, would you. Bonus points if you weren't allowed anaesthesia as that affects the regrowth.

What the side effects are. One would(perhaps naively) assume that regeneration is an obvious survival advantage, and that losing regenerative capabilities would be a handicap. That being so, one would tend to suspect that an anti-regeneration gene would be fairly strongly selected against. Since this gene is, in fact, rampant in mammals, one is led to the suspicion that there must be some sort of upside.

Is it something more or less irrelevant to modern humans(at least those wealthy enough to ever be genetically engineered), something like "without any sort of medical care, most serious injuries were fatal before regeneration could occur, so the extra energy costs weren't worth it", or is it some kicker of the "Well, without a whole bunch of other adaptations possessed by certain amphibians and creepy-crawlies, you'll 'regenerate' yourself entirely full of tumors by age 20." flavor?

Think of it this way: MOST of the time, your body tries mightily to STOP things from growing - those are typically cancers (uncontrolled cell division). It may have been easier in the evolutionary sense to shut down regeneration than to deal with it's consequences.

I second this. p21 is what you call a 'tumor suppressor' gene. Without p21 it is significantly easier to get cancer. It would matter less to mice, because of their short lifespan and different DNA damage repair strategy (fix aggressively active genes, don't care much about the rest). For humans with life span ten times longer compared to mice, this is real deal breaker. These mice also appear to have some sort of autoimmune disease.

Think of it this way: MOST of the time, your body tries mightily to STOP things from growing - those are typically cancers (uncontrolled cell division). It may have been easier in the evolutionary sense to shut down regeneration than to deal with it's consequences.

Agreed, but this line from the article is very iteresting:

Heber-Katz said. "In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported." In fact, the researchers saw an increase in apoptosis in MRL mice -- also known as programmed cell death -- the cell's self-destruct mechanism that is often switched on when DNA has been damaged

So I guess the question is whether programmed cell death has certain other consequences.

It's incredibly funny to watch all the well-fed deep thinkers here scratch their heads and try to come up with complicated solutions to a trivial problem: cold blooded animals don't have to keep eating on a daily basis to survive. Ergo, they have time to regenerate. They can just find a place to curl up while it happens.

Warm blooded animals need a much more regular food supply. Ergo, there is an advantage to them in a fast and adequate healing.

One would(perhaps naively) assume that regeneration is an obvious survival advantage, and that losing regenerative capabilities would be a handicap. That being so, one would tend to suspect that an anti-regeneration gene would be fairly strongly selected against. Since this gene is, in fact, rampant in mammals, one is led to the suspicion that there must be some sort of upside.

We can't synthesise vitamin C either, but there's no benefit to that. Almost all other animals can synthesise it, but we get scurvy and die unless we ingest it.

If it doesn't kill you before you can reproduce, and it doesn't make you infertile, it can be passed on. We lack that ability because one of our ancestors lacked it, but survived and reproduced regardless.

Because of that low standard for selection, it's relatively easy for a trait to be irrelevant to the selection process, good or bad.

If on the other hand you make the presumption that an ancestor species had it, then you might wonder why we lost that ability. Sure, it might not affect survivability before age of reproduction either way. But then why did only those without the ability survive?

What the side effects are. One would(perhaps naively) assume that regeneration is an obvious survival advantage, and that losing regenerative capabilities would be a handicap. That being so, one would tend to suspect that an anti-regeneration gene would be fairly strongly selected against. Since this gene is, in fact, rampant in mammals, one is led to the suspicion that there must be some sort of upside.Is it something more or less irrelevant to modern humans(at least those wealthy enough to ever be genetically engineered), something like "without any sort of medical care, most serious injuries were fatal before regeneration could occur, so the extra energy costs weren't worth it", or is it some kicker of the "Well, without a whole bunch of other adaptations possessed by certain amphibians and creepy-crawlies, you'll 'regenerate' yourself entirely full of tumors by age 20." flavor?

Well, FTFA: "In normal cells, p21 acts like a brake to block cell cycle progression in the event of DNA damage, preventing the cells from dividing and potentially becoming cancerous," Heber-Katz said. "In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported."In fact, the researchers saw an increase in apoptosis in MRL mice -- also known as programmed cell death -- the cell's self-destruct mechanism that is often switched on when DNA

The next step is to make some p21 specific RNA interference molecules and shut it down in an adult, non-regenerative mouse. Then clip its ear and see what happens.Since it also increases apoptosis, would this make a good diet pill?

Screw that. 6.5+ billion people on this planet, many with a propensity toward cutting, scarring, beating, or even killing themselves, and we can't find just one who will volunteer to have this done so that we can see what will happen in a human? Christ, I could find a couple of dozen people in the next hour who would be willing to go on a suicide mission to Mars. Doing this kind of thing to an unwilling victim is straight-up evil, but finding volunteers really can't be that hard. Let's just answer the real

This is, obviously, the holy grail for many injuries and holds out immense hope for amputees etc. etc. There's one thing about it that has me concerned. Darwinism is cruel. It causes the weak to fall by the wayside of evolution and the strong to perpetuate the best of the species. Nature does things for a reason. The question in the back of my mind is: if we fool with this, what are the underlying natural reasons for the gene to be turned off? We aught to be taking a very close look at the consequences of t

I can think of a couple reasons why this feature may have been dropped. nutrition (regrowing something is a hell of a lot more resource intensive than just closing the hole) and infection prevention (just closing the hole is a lot faster than regrowing something, so less chance of it getting infected). Both of these were relevant considerations very recently and evolution is pretty slow.

I think you have an interesting point here on the resource requirements of regeneration. Part of the obesity problem is that our bodies evolved to store whatever they couldn't use right now for later, so it stands to reason that such things were "turned off" for efficiency's sake. We didn't necessarily evolve in a land of plenty

Sure anyone with even a vague knowledge of evolution and basic highschool genetics will worry, but as long as they make vague promises like bigger dicks, hair regrowth and weight loss pills, they won't have any problems.

Consider this: we can (and do) save many children with birth defects, often we are succesfull enough so that they can leard normal life (and even be oblivious to any issues). Problem is that some of theese defects are hereditary. Guess what? Next generation is worse off as far as ratio of defects is concerned.

We obviously will never do "sparta" thing and kill of children society finds undesirable. Nor will anyone with genetic defect be prevented from having chil

The only reason that mammals with an active p21 gene and the inability to regenerate tissue continued on and p21 suppressed mammals did not is because chicks dig scars. No perfectly healthy scarless male is going to attract a hot chick who is only interested in the dummy injury prone type.

Somewhat not being able to regenerate (or something deeply related with that) gave us an evolutionary advantage. Is pretty tempting to just make pills to turn that off, but what will be the cost? Don't think that you will fall into not being able to get older or make new memories, but still stinks to too good to be true.

...in practice, do we have the technology to knock this gene out in humans? That's the key thing. Either you have to engineer every human to have the gene before birth, or you have to do a live fix. And a live fix has all sorts of complications.

Of course, I'm completely ignoring potential side effects. This is best if you imagine a drug for it being advertised: "Regrowitol may cause side effects including cancer, accessory limbs, mutation into evil lizard creature..."

A lot of people are asking why evolution has taken away our regenerative capacities, and are guessing what the downside of this regeneration is.

P21 is involved with anti-cancer. It arrests the cell cycle when DNA damage occurs, allowing the damage to be repaired (so mistakes are not carried forward into new generations). Or if the damage is too severe, the cell is made senescent (they lose the ability to reproduce and instead lead out a gentle retirement, performing their normal job until they just die of old age)

P21 knockout mice show a lot of carcinomas and P21 is also up-regulated by and works to remedy excessive oxidative stress. It's very unlikely this research is going to lead to a pill that knocks out P21 and lets us grow limbs back. It will only lead to a greater understanding of how our pathways work.

Heber-Katz said. "In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported." In fact, the researchers saw an increase in apoptosis in MRL mice -- also known as programmed cell death -- the cell's self-destruct mechanism that is often switched on when DNA has been damaged

My guess is that while not having this gene results in wonderous regenerative abilities, it'll also increase your chances of developing cancer before the age of 20 by a bajillionfold. Not a problem for mice, but certainly a problem for men.

It is unlikely that a process so complex as mammalian tissue regeneration be controlled by a single gene. Moreover, p21 mutations have been associated with cancers. Which brings forth another question: why is it that only "lower" organisms (and mammalian fetuses) are capable of scar-less tissue regeneration? The answer is yet to be discovered but it is very likely that evolution had to stroke a balance between cancer control and tissue regeneration. It won't be easy to figure out "the way back" to regeneration, or even to avoid the risks of such a path.

Well, they claim that they thought it was "lost to evolution"... I assume the fact that the gene is not active today is the result of evolution. So that implies the question Why is it inactive? I would think the ability to regenerate body parts on demand would be an evolutionary advantage, wouldn't it? So something must not work correctly (or there must be some kind of side effect)... It could be as simple as we didn't have enough nutrition at the time to be able to support it, and would die of malnourishment when we'd otherwise live with the injury... But I do agree, it does seem "too easy". They must be a negative here that we haven't figured out... I guess it's time to welcome our new self-healing mouse overlords...

Not all mutations are good. Some mutations are bad. Sometimes multiple mutations occur at the same time... Maybe another highly beneficial mutation occurred at the same time as this one was lost... Imagine losing a limb... Not as easy to run away from predators while your limb is growing back... May not have been advantageous enough..

This might be true, the bad mutation might even be non fatal but that is not really the point. The thing to consider is the evolutionary advantage (or disadvantage) it gives. I would think that bad mutations give an evolutionary disadvantage and thus be selected against. So the question really is... "What sort of evolutionary advantage does it impart?" I really don't know the answer and I suspect that the researchers are just beginning to answer that question.

If simply switching off the one gene is enough to allow regeneration, then it WOULD happen with an incidence similar to other single base pair change genetic defects. Something else is going on here. It could be that larger animals with the gene turned off die in the womb or something.

Or perhaps most common injury is just a small scratch, not losing your limb. Even the result looks nasty, faster healing offers one very important benefit. Open wounds tend to infect and that can cause serious illness or even death without modern medicine. It is not hard to imagine that healing your wounds a day or two faster would decrease the chance of getting sick a big time.

I would think the ability to regenerate body parts on demand would be an evolutionary advantage, wouldn't it?

Not necessarily. A lot of small animals are pretty much disposable: they're sufficiently fragile that there's only a very narrow boundary between a trivial injury and a fatal one. (And anyone who's kept small birds and animals will know that if they're hurt beyond a certain point they'll simply go into shock and die.)

So it's entirely plausible that the gene might have been caused by a spot mutation very early on while all mammals were basically mice, and it then had a sufficiently small effect on actual survivability that the trait didn't get bred out. Later, once the small, disposable animals turned into large, expensive ones, it was too late.

It is interesting that both birds and animals appear to lack this trait, though. We both descend from much the same sort of lizards but in different directions. Finding out exactly where this gene sequence appeared might be productive.

(Of course, I want to know when we'll be able to get gene therapy to suppress the gene. Assuming it works in humans, and that the gene doesn't do anything else critical, it might even be fairly straightforward! But probably won't happen soon and I'm certainly not volunteering to be the guinea pig...)

In case of large animals it may take very long to replace the lost body part. Maybe adaptation is simply faster, and more energy efficient. Same probably for grievous wounds. Or maybe it's just not worth it at all, and the time it took to replace or get over such injury resulted in death of both. But the suppressed gene code was easier to write? Damn lazy programmers...

In case of large animals it may take very long to replace the lost body part. Maybe adaptation is simply faster, and more energy efficient. Same probably for grievous wounds. Or maybe it's just not worth it at all, and the time it took to replace or get over such injury resulted in death of both. But the suppressed gene code was easier to write? Damn lazy programmers...

Lose a limb, and you can still survive. Starve to death because you were putting a LOT of energy into making a new limb...

Well, they claim that they thought it was "lost to evolution"... I assume the fact that the gene is not active today is the result of evolution. So that implies the question Why is it inactive? I would think the ability to regenerate body parts on demand would be an evolutionary advantage, wouldn't it?.

Supposedly around 8% of human DNA was inserted by viruses [popsci.com] into our genome. It could be that a virus in the past messed up our ancestor badly enough to lose regeneration and killed of all the rest. Also evolution doesn't have a "goal" our non-regenerative ancestor was just lucky that through some trait it was the best adapted to the environment at the time and it survived. It doesn't mean regeneration had a negative side to it.

Evolution is 'good enough'. Meaning it isn't perfect, and if you can still produce, then it's successful. It could just be off by chance. If I were to make a wikld guess, I would say that this way takes more energy then are current way of healing. So it 'fell' out of use and there hasn't been in random mutation that turned it on and provided a substantial advantage over out current environment.